The objective of this proposal is to determine the changes in synaptic structure and function which underlie a reduced capability to sustain synaptic transmission in the nervous system of aged animals. This entails comparisons of presynaptic transmitter release, postsynaptic receptor sensitivity, and nerve-terminal ultrastructure in the phrenic nerve-diaphragm muscle preparation of aged and control, young rats. To determine if extracellular accumulation of potassium is more pronounced during senescence, leading possibly to axon conduction block and synaptic depression, ion-sensitive electrodes will be used to monitor extracellular potassium concentrations in the end-plate regions during repetitive activity. By applying acetylcholine iontophoretically, the postsynaptic response to transmitter will be examined in rats from both age groups; junctional sensitivity, desensitization, supersensitivity, and membrane conductance will be measured. The amount of ACh present in the presynaptic terminals and the amount released by an action potential will also be estimated by a radiochemical assay. The choline by-product of hydrolyzed ACh will be converted to labeled, choline phosphate; the quantity will then be measured on a scintillation counter. The morphological correlates of transmission in these preparations will also be examined. Using a cholinesterase stain, the synaptic contact area will be estimated in both aged and control rats. The number and the distribution of synaptic vesicles within the nerve terminals will be measured and compared.